Month: January 2018

Our 1st prize winner is:

Kathleen Bailey

Originally from Somerset, Kathy is currently in her third year studying Biomedical Sciences at University of Manchester. She has had ambitions of going into cancer research throughout the course of her degree, so is intending on further study post graduation. Next year, she hopes to be studying a Master’s degree with the intention of PhD study afterwards. Congratulations, Kathy!

Cancer Research: Why we should ignore what we already know

One of medicine’s biggest challenges in the modern world is the fight against cancer. Nearly every person on the planet will have an experience with cancer of some description, which emphasises the scale of the impact of the disease and the devastating consequences that come with it. In the field of biomedicine, cancer research is one of the most exciting, yet challenging of its divisions. Researchers are discovering new mechanisms and pathways which enrich our understanding of the ways in which cancers can proliferate and sustain, however we still have a long way to go before we can overcome this deadly disease.

There are many different ways in which cancers manifest in the body, and as a result there are many different obstacles to overcome when considering therapeutic research. Much has focussed on the six biological hallmarks which are considered homologous in all cells defined as cancerous (Hanahan and Weinberg, 2011), however more recent research has pinpointed mechanisms unique to individual cancers, which may provide better treatment for sufferers. A prime example of this is ongoing research into pancreatic ductal adenocarcinoma (PDAC).

PDAC is known as one of the most aggressive forms of cancer, and is one of the least well understood. Gemcitabine and fluorouracil chemotherapies, along with pancreatectomy surgeries are often rendered unsuccessful due to a number of factors contributing to the aggressive nature of the disease, such as difficulty in early detection and strong metastatic activity in early stages of the disease. Four critical gene mutations have been defined (KRAS, CDKN2A, P53, SMAD4) and the role of inflammation has been touched upon by laboratories amongst a number of discoveries, yet the survival rate of PDAC has failed to improve over the past 40 years, and remains at a steady 5% (CRUK, 2017).

Researchers have found aspects of PDAC pathophysiology that contradict some of the things we accept to be true about cancer cells and their behaviour, and others that appear to be unique to this particular cancer. For example, rather than increased angiogenesis surrounding the tumour, there seems to be decreased vascularisation, and the extracellular matrix consists of a heterogenous stroma, which reduces treatment viability by limiting drug delivery to the tumour. As a result of this and other recent findings, many labs working on PDAC have moved their attention to targeting the stroma and the mechanisms through which it sustains tumours of the pancreatic ducts, and exploiting the unusual lack of vascularisation to improve chemotherapy (Gore and Korc, 2014).

These breakthroughs suggest perhaps the direction to be heading in with cancer research is to identify unique aspects of each cancer and target these directly, rather than using broad spectrum approaches. Cancers should be treated as unique to organs or systems and therefore treatments need to be refined using new, unorthodox approaches. For example, manipulating upstream open reading frames with respect to the DNA sequence of a particular cancer to influence proliferative activity – such as the ERCC5 polymorphism identified in carcinoma cells, or identifying stem cell niches within particular tumour regions to target the origin of sustained proliferation (Yang, 2011).

Following these breakthroughs, and with help from the power of multiple approaches to research, we have the ability to be steps away from beating cancer once and for all.

Our 2nd prize winner is:

Diya Kapila

Diya is in her final year at Imperial College School of Medicine, where she undertook a BSc in Gastroenterology and Hepatology. She has worked as an academic researcher exploring the microbiome and its role in Clostridium Difficile infection. In the future, she hopes to pursue an academic clinical career in medicine. Congratulations, Diya!

Microbiome and Cancer: a Promising Future

This decade, the thrilling evolution of novel systems biology technologies has allowed us to explore the nexus between health and disease with greater innovation and scrutiny than ever before. Through metabonomics, metabolite exploration of biofluids, and metagenomics/metataxonomics, quantifying structure and functions of bacterial communities (1), the pronounced role of our microbiome in carcinogenesis, immune-surveillance and disease is becoming highly evident. Yet its vast future role in cancer investigation and treatment remains largely uncertain, with several important questions still to be answered.

Research purporting to the importance of our gut microbiome in various diseases, including Crohn’s disease, asthma and diabetes, is widely recognised. However, we are now gaining an appreciation of the complex interplay between our microbiome, inflammation and cancer: colorectal carcinogenesis is a notable example where gut F. nucleatum, B. fragilis, S.bovis and E. coli appear to play an active role (2). Another interesting facet of our microbiome is its relationship with our bile acid composition and pool size. Disturbance to this equilibrium can lead to numerous gastrointestinal cancers: research links cirrhosis, faecal bile acid concentrations and gut microbiota composition (3); and microbiota-mediated production of deoxycholic acid is associated with hepatocellular carcinoma (4). Interestingly, recent evidence shows that our gut microbiota play a further role, to enhance tumour immune-surveillance (5). It is now being shown that even cancer therapies, including oxaliplatin and cyclophosphamide efficacy are affected by distinct microbial environments (5). This renders the question: could we manipulate our microbiome to enhance chemotherapy in the future? The ability to modify our microbiome is remarkable, notably through probiotics, diet, antibiotics and age- perhaps now we could use this knowledge to alter it as a medical adjuvant to treatment, or even as a treatment itself.

Despite acquiring the tools and the interest to develop new microbiome therapeutics, multiple questions and challenges still remain unaddressed. Unearthing the ‘good’ bacteria from the ‘bad’ is one immense challenge; it is hard to identify whether all these reported microbiome alterations are the cause or effect of carcinogenesis. Furthermore, manipulating our microbiome may have unwanted effects on other disease states or major safety implications (6). If we were to resolve these initial difficult questions, through initial honing of bacterial profiling and function, we would be one step closer to creating innovative screening tools, biomarkers and exciting therapeutics.

It is most definitely an enthralling, but challenging, time for novel system biology technologies and scientists are now beginning to fully uncover the inescapable significance of “microbiome immune-oncology” in cancer treatment and prevention.

Our 3rd prize winner is:

Isabella Withnell

Isabella is in her final year at Imperial College London where she is studying Biochemistry. Throughout her time as an undergraduate she has become particularly interested in cancer research and spent last summer working for Cancer Research UK. Congratulations, Isabella! Read her entry below:

Long non-coding RNA and its “lnc” to Prostate Cancer

Despite much research, prostate cancer still represents a major cause of morbidity and mortality in males, warranting a new avenue of investigation. In parallel, this decade, long non-coding RNAs (lncRNAs) have risen from obscurity and are now known to be major regulators of gene expression. LncRNAs have been identified that regulate tumour suppressor genes, oncogenes and the androgen receptor signalling pathway; three important processes that can drive the progression of prostate cancer (PCa) if misregulated. In this essay I will discuss two recently identified prostate cancer-associated lncRNAs: HOTAIR and SChLAP1.

It has been known that PCa is an androgen driven disease since the discovery by Huggins and Hughes in 1941. Androgen-depletion therapy is the primary treatment for advanced PCa(1). However, after 2-3 years the cancer progresses to castration-resistant prostate cancer (CRPC) due to AR hyperactivity(2). The AR is a nuclear receptor that translocates into the nucleus after binding an androgenic hormone where it acts as a transcription factor, regulating a large repertoire of genes key to the behaviour and fate of prostate cancer cells(3). HOTAIR, is an androgen-repressed lncRNA that is significantly upregulated in CRPC cell lines(4). Subsequent experiments demonstrated that HOTAIR binds the N-terminal domain of the AR protein, which prevents the E3 ubiquitin ligase, MDM2, from binding. This prevents AR degradation thereby increasing the stability of AR. As a result, HOTAIR induces androgen-independent AR activation, a major cause of CRPC(4).

SChLAP1 is an intergenic lncRNA transcribed from a gene desert located on chromosome 2(5). Studies have reported that SChLAP is one of the best prognostic indicators of lethal prostate cancer and can be used clinically as a urine-based biomarker(5). SChLAP1 co-immunoprecipitates with a component of the SWI/SNF complex and prevents it binding to DNA(5). SWI/SNF is a conglomerate that remodels chromatin especially at promoters to increase access to DNA for transcription(6). This explains why SChLAP1 overexpression reduces the expression of tumour-suppressor genes.

Research into the lncRNAs involved in PCa has only just commenced and already studies have shown that they play key roles in disease pathogenesis and progression. The mechanisms by which lncRNAs control chromatin is becoming a hot topic in genomics due to the potential of lncRNA, due to its unique properties, to affect chromatin in ways that proteins cannot. The lncRNAs discussed have distinct expression patterns that can serve as biomarkers for PCa diagnosis and prognosis as well as potential drug targets. While lncRNAs are already being used as diagnostic biomarkers, a more thorough understanding of their functions and mechanisms in PCa pathology is required before therapeutics are developed. This may require advances in the experimental techniques used to study lncRNAs to overcome the reproducibility issues that have plagued lncRNA research.